Accumulating evidence shows that deregulation of PI3K and PTEN signaling is important in human prostate cancers. However, the mechanisms of PI3K-induced and PTEN-inhibited prostate tumor growth are not known. The long-term objectives of this proposal are to understand the molecular mechanisms of prostate tumorigenesis due to deregulation of the PI3K and PTEN pathway, and to elucidate the connection of PI3K and PTEN downstream signaling components to tumor angiogenesis in vivo. We hypothesize that PI3K regulates prostate tumorigenesis by inducing angiogenesis in the developing tumor and by activating unexploited targets and mediators for inducing prostate tumorigenesis. Specific Aim 1 is designed to identify the mechanisms and new functions of PI3K and PTEN effectors that regulate prostate tumorigenesis using our established tumor models. This aim will study the effects of PI3K and PTEN in prostate tumor growth, test the role of angiogenesis in PI3K-induced tumor growth, and search for novel functions of PI3K effectors involved in prostate tumor growth and angiogenesis. Specific Aim 2 is designed to characterize PI3K downstream signaling molecules to transmit PI3K signals for inducing prostate tumor growth and angiogenesis. We will determine whether AKT transmits the oncogenic signals from the deregulation of PI3K and PTEN signaling, and whether AKT in turn activates p70S6K1 and MDM2 in inducing prostate tumor angiogenesis in vivo. Since we found that MDM2 is upregulated by PI3K and AKT in cultured prostate cancer cells in our preliminary study, the study of MDM2 in PI3K- and AKT-induced prostate tumorigenesis and angiogenesis will help us to understand novel mechanisms of MDM2 expression in transmiting PI3K and AKT signals for inducing the tumor angiogenesis. This work will identify new functions of PI3K effectors in prostate tumorigenesis and angiogenesis, reveal mechanisms of PI3K signaling in regulating prostate tumorigenesis, and help to establish rational therapeutic strategies for human prostate cancer by targeting specific signaling molecules in the future.